Composition and method for treating wounds

ABSTRACT

Provided, among other things, is a method of treating a wound comprising: periodically applying to the wound over a course of days an effective amount of a water based formulation (comprising: 0.5 to 5 wt % of an emollient comprising silicone oil, 2 to 10 wt % of fatty acid, humectant(s), emulsifying agent(s), and polymer(s)), wherein the formulation is formulated as a spray, cream, lotion, milk or foam-former.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/406,804, filed on Oct. 26, 2010, the content of which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to a water-based composition of siliconeoil, fatty acid(s), and humectant(s), which can be used to treat skinand soft tissue wounds, ulcers, burns, various types of dermatoses,inflammatory conditions of the mucosa, and the like.

A foamable composition similar to those described herein is described inU.S. Pat. No. 5,993,830. The composition has been used with subjectshaving chronic hand eczema. What was not described, and what has nowbeen unexpectedly discovered, is that such compositions can acceleratehealing of wounds and control inflammation.

SUMMARY OF THE INVENTION

Provided, in one embodiment, is a method of treating a wound comprising:periodically applying to the wound over a course of days an effectiveamount of a water based formulation (comprising: 0.5 to 5 wt % of anemollient comprising silicone oil, 2 to 10 wt % of fatty acid,humectant(s), emulsifying agent(s), and polymer(s)), wherein theformulation is formulated as a spray, cream, lotion, milk orfoam-former.

Also provided is a method of treating an inflammatory condition ofmucosal tissues comprising: periodically applying to the inflammatorycondition over a course of days an effective amount of a water basedformulation (comprising: 0.5 to 5 wt % of an emollient comprisingsilicone oil, 2 to 10 wt % of fatty acid, humectant(s), emulsifyingagent(s), and polymer(s)), wherein the formulation is formulated as aspray, cream, lotion, milk or foam-former.

Further provided is a method of treating a dermatoses comprising:periodically applying to the dermatitis over a course of days aneffective amount of a water based formulation (comprising: 0.5 to 5 wt %of an emollient comprising silicone oil, 2 to 10 wt % of fatty acid,humectant(s), emulsifying agent(s), and polymer(s)), wherein theformulation is formulated as a spray, cream, lotion, milk orfoam-former.

Additionally provided is a formulation comprising: 0.5 to 5 wt % of anemollient comprising silicone oil, 2 to 10 wt % of fatty acid, 0.25% to4% alkyl pyridinium chloride surfactant, humectant(s), emulsifyingagent(s), and polymer(s); wherein the formulation is formulated as aspray, cream, lotion, milk or foam-former.

Further provided is a method of reducing the risk of infection from askin or mucosa piercing procedure comprising: applying to the skin ormucosa to be pierced an effective amount of a water based formulation(comprising: 0.5 to 5 wt % of an emollient comprising silicone oil, 2 to10 wt % of fatty acid, humectant(s), emulsifying agent(s), andpolymer(s)), wherein the formulation is formulated as a spray, cream,lotion, milk or foam-former; and piercing the skin or mucosa.

DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, the formulation of the invention provides anon-irritating composition. Irritation, in certain embodiments, ismeasured by ISO 10993-10: 2002 Standard, “Biological Evaluation ofMedical Devices, Part 10-Tests for Irritation and Sensitization,” pp.6-10, 21, which testing method is incorporated herein by reference. Inparticular, for each test site on shaved dorsal skin of an albinorabbit, gauze incorporating 0.5 mL of test material or negative controlmaterial is applied. One test and one control site are used on each sideof the paravertebral skin. The infused gauzes are covered withtape-backed gauze. The trunk of the rabbit is wrapped in elastic bandagesecured by hypoallergenic tape. After a minimum of 24 hours, thecoverings are unwrapped. Observations are made at 60 min±2, 24 h±2, 48h±2 and 72 h±2 post unwrapping. Tissue reactions are rated for grossevidence of erythema and edema.

For a given rabbit, values for each test site and each of the 24 h, 48 hand 72 h measurements are totaled, and divided by six (2 tests sites×3measurements). Control values were treated in the same way. For allrabbits, these test values were summed, normalized against the summedvalues for the negative controls, and divided by the number of animals.A negligible, slight, moderate or severe response is categorized basedon the Primary Irritation Index:

Response Category Comparative Mean Score Negligible   0 to 0.4 Slight0.5 to 1.9 Moderate   2 to 4.9 Severe 5 to 8

By “non-irritating” it is meant that compositions according to thisembodiment of the invention elicit a negligible Primary IrritationIndex.

The non-irritating quality of these embodiments is surprising in view ofthe surfactants often found in these embodiments. While not being boundby theory, it is believed that water and appropriate selection ofrelatively mild surfactants, as illustrated herein, may contribute tothe non-irritating quality of the wound-treating composition.

Irritation, in certain embodiments, is measured by the 21-Day CumulativeIrritation procedure, originally introduced by Lanman et al. (JointConference on Cosmetic Sciences, the Toilet Goods Association (now namedThe Cosmetic, Toiletry and Fragrances Association) Wash. D.C., Apr.21-23, 1968), that has been successfully employed as a test forcomparing the irritation potential of mild to moderately irritatingtopically applied skin care products. The procedure involves dailyconsecutive applications of occlusive patches to human skin over a21-Day period. Each of the patches applied is worn for approximately 24hours, removed under supervision and the sites scored by a trainedevaluator.

The relative cumulative irritation potential of topically applied testarticles can be compared to a negative (Johnson's® Baby Oil) and apositive (0.2% v/v sodium lauryl sulfate) control following repetitivedaily applications to the skin of normal, healthy adult volunteers. Thetest articles, in addition to Johnson's® Baby Oil and 0.2% sodium laurylsulfate (v/v in DI water) are rubbed in to the upper back between theleft and right infra-scapular areas and then covered with a blanksemi-occlusive patch. Test article application sites are randomized tolimit site bias. Products are rubbed in and blank semi-occlusive patcheswere applied to the same sites every day for twenty-one (21) consecutivedays for a total of 21 applications. Each patch is worn forapproximately 24 hours, removed under clinical supervision and the testsites evaluated approximately 10 minutes following patch removal. If adermal reaction of a 3-level or greater occurs with any of the testarticles at any point during the study, further patch testing on thatsubject at the test site involved is terminated and the observed scoreis assigned to that site for all remaining scheduled test days (i.e.,last score observed carried forward). If a test site is discontinued forreasons other than a dermal reaction of a 3-level or greater (due toerosion, scabbing, etc.), an erythema score of 3 and any other alphacharacter associated with the score is imputed and assigned to that sitefor all remaining scheduled test days. If a test subject exhibits asignificant degree of irritation to the adhesive such that patchreapplication is not feasible, the test subject is discontinued from thestudy and the scores for this subject were not used in determining thecumulative irritation totals. When warranted, individual sites arediscontinued due to tape reaction (i.e., tape dermatitis) and are notused in determining the cumulative irritation totals. Individual testarticle scores are calculated via summation of the results for each day.Subjects receive 21 rub-in applications of 0.2 mL of the test articles(including controls) to both sides of their back during the course ofthe study. Total cumulative irritation scores are determined for eachtest article by summing the daily erythema scores for each subject.

In certain embodiments, the wound-treating composition of the inventionhas a “non-greasy feel” when applied. A non-greasy feel is measured inreference to a comparison of the feel of the Example 1 composition(non-greasy standard) of U.S. application Ser. No. 12/016,371, filedJan. 18, 2008 (US2008/175793), applied to skin at 1 mg/cm², compared tothe oil-based product described in the Table at Column 3 of U.S. Pat.No. 5,919,470 (Bradley Pharmaceuticals, Inc., greasy standard), appliedin the same amount. Application includes working the wound-treatingcomposition into the skin. While the feel of compositions of theinvention may vary, in making the comparison between the non-greasystandard, the greasy standard, and the prospective non-greasycomposition, it will be apparent which category the prospectivecomposition falls within. The non-greasy skin feel may be moist andsmooth feeling, but the difference in greasy feel relative to the greasycomparative shall be clear.

In certain embodiments, the wound-treating composition of the inventionhas a “non-watery feel” when applied. A non-watery feel is a feel muchlike that of the Example 1 composition (non-watery standard) of U.S.application Ser. No. 12/016,371, filed Jan. 18, 2008 (US2008/175793),applied to skin at 1 mg/cm². A feel that, in contrast, is noticeablymore watery is disqualified.

In certain embodiments, the formulation of the invention provides anon-sensitizing composition. Sensitization, in certain embodiments, ismeasured by ISO 10993-10: 2002 Standard, “Biological Evaluation ofMedical Devices, Part 10-Tests for Irritation and Sensitization,” pp.6-10, 21, which testing method is incorporated herein by reference.Dermal sensitization testing for topical products places into differentcategories based on their potential to cause dermal sensitization inguinea pigs and extrapolating the results to humans.

In the Induction Phase, ten test guinea pigs are patched with acomposition of the invention and 5 guinea pigs are patched with thenegative control article, removed after at least 6 hour exposure. Aftera 24-hour rest period, each site was observed for erythema and edema.The procedure is repeated 3 times per week for 3 weeks. In the ChallengePhase, following a 2 week rest period, the animals are topically patchedagain, removed after at least 6 hours of exposure. Dermal patch sitesare observed for erythema and edema 24 and 48 hours after patch removal.Each animal is assessed for a sensitization response and test resultswere based upon incidence and severity of the sensitization reaction.

Certain embodiments involve the treatment of “partial thickness wounds,”which for the purposes of this application are those that involve theepidermis and at least a portion of the dermis. Wound healing ismeasured in the pig model by International Standards Organization (ISO)Guidelines 10993-1 (2003), 10993-2 (2006), 10993-4 (2002), and/or10993-6 (2007). This kind of study is conducted to determine the effectscompositions of the invention applied topically on wound healing in asplit thickness skin graft model in the pig. Domestic Yorkshirecrossbred swine undergo a single surgical procedure during which sixsplit thickness skin graft wounds were created using a dermatome on thedorsum, three wounds on either side of the dorsal midline. Each site istreated with one of three treatments, Standard Care Dressing(non-adherent absorbable dressing, Johnson & Johnson), Positive Control1 (Biafine Ointment), or the Test Article (ProDerm—Hydrometic Foam). Thetopical treatments are applied topically to wound sites once daily for14 days at a dose volume of approximately 4 mg/cm² (approximately 25mg). Observations for morbidity, mortality, injury, and the availabilityof food and water are conducted, for example, twice daily. Clinicalobservations are for example conducted weekly. Body weights are measuredand recorded pretest and (for example) weekly. Physical examinations areconducted pretest. Blood samples for clinical pathology evaluations arecollected from all animals pretest. Wound sites of all animals areevaluated for healing and photographs were obtained from all animals onDays 1 (evaluation only), 4, 7, 10 and 14. Wound measurements areperformed in the wound area for all animals on Days 4, 7, 10, and 14. Atstudy termination, complete necropsy examinations are performed andselected tissues were microscopically examined.

In certain embodiments, the formulation of the invention isnon-comedogenic where the method of measuring comedogenicity is amodification of that described by Dr. Otto Mills (Mills et al., Archivesof Dermatology 118: 903-905, 1982). For example, one of the compositionsof Table A (described below) was tested using this model. Testing canbe, for example, in a single center, test site randomized studycomparing the ability of the composition to induce microcomedoneformation relative to a•positive (Acetulan™) and a negative (BlankPatch) control. Approximately 0.2 mL of the composition and the positivecontrol are applied to blank semi-occlusive patches (TruMed™ patchescontaining needle punch absorbent cotton and Alpharma Scantape, BradyMedical, Mesquite, Tex.) and these patches, along with a negativecontrol (blank semi-occlusive patch), are applied to the upper backbetween the left and right infra-scapular areas. Patch application sitesare randomized as to their position on the subjects' backs to eliminatetest site bias. Patches are applied three times a week (e.g., everyMonday, Wednesday and Friday) for twelve patch applications (i.e., 4weeks) to the designated test sites. Subjects are instructed to wear thepatches continuously for 48 hours following the first and second weeklypatch applications and continuously for 72 hours after the third patchapplication. The sites were scored for the presence of erythemaaccording to an agreed upon scale.

At the final visit, after all patches are removed and the test sites arescored for erythema, follicular biopsies of the sites were collectedusing a cyanoacrylate follicular biopsy technique. Follicular biopsiesare examined under a stereo microscope and the number of microcomedonespresent on the slides counted. The number of microcomedones present atthe treated test sites are compared to that observed for the positiveand negative control sites to determine significance. The negativecontrol should significantly less microcomedones than the positivecontrol to a high statistical confidence (e.g., P≦0.05). Where thenumber of microcomedones at the sites treated with the test compositionare not significantly different from the number of microcomedonesobserved at the negative control sites, the test composition is“non-comedogenic.”

The compositions of the invention can be used to treat dermatoses(inflamed skin) and skin wounds. For the purposes of the claims,“dermatoses” that can be treated with the compositions of the inventioncan either be an acute or a chronic inflammatory condition of the skinincluding atopic dermatitis or radiation dermatitis. For this purpose,eczema, irritant contact dermatitis and allergic contact dermatitis arenot a dermatoses. For the purposes of the claims, a “wound” that can betreated with the compositions of the invention is an acute or chronicpartial or full thickness skin or soft tissue wound including incisions,abrasions, lacerations, penetration wounds, burns, ulcerations, andsurgical wounds.

Mucosal tissues that are candidates for treatment include, for example,esophageal mucosa, rectal mucosa, anal mucosa, urethral mucosa, vaginalmucosa, external mucosa, oral mucosa, and the like. Inflammatoryconditions of mucosal tissues can be treated with the compositions ofthe invention. Such conditions include, for example, gingivitis,mucositis (including as a consequence of chemotherapy or radiotherapy),anal fissures, and the like.

To treat the wound indications of the invention, an “effective amount”of the composition will be recognized by clinicians but for woundsincludes an amount effective to accelerate healing to a degreecomparable to Biafine Ointment. In certain embodiments for treatingwounds, the effective amount is effective to accelerate healing to adegree superior to Biafine Ointment. To treat the mucosal indications ofthe invention, an “effective amount” of the composition will berecognized by clinicians but includes an amount effective to treat,reduce, alleviate, ameliorate, eliminate or prevent one or more symptomsof the disease sought to be treated or the condition sought to beavoided or treated, or to otherwise produce a clinically recognizablefavorable change in the pathology of the disease or condition. To treatthe dermatoses (e.g. dermatitides) of the invention, an “effectiveamount” of the composition will be recognized by clinicians but includesan amount effective to treat, reduce, alleviate, ameliorate, eliminateor prevent one or more symptoms of the disease sought to be treated orthe condition sought to be avoided or treated, or to otherwise produce aclinically recognizable favorable change in the pathology of the diseaseor condition. In all treatments, an effective amount can be effective toaccelerate reduction in symptoms to a degree comparable to, or superiorto, Biafine Ointment.

Generally, the formulation of the invention is applied two to threetimes a day to the affected tissue, in amounts of 1 to 5 mg/cm², or asneeded or prescribed.

For certain indications of the mucosa, the foam or gel form may often beselected due to the greater ease in assuring coverage of the affectedtissue.

In certain embodiments using the foam form, the foam is a stable foam,meaning that when applied to the skin at one of 1, 2 or 3 mg/cm² and notworked into the skin, the foam remains a stably adherent foam for 30seconds or more. In some cases, the foam remains a stably adherent foamfor 60 seconds or more, 120 seconds or more, 150 seconds or more or 180seconds or more. Though stable, the foam can be worked into thepatient's skin.

In certain embodiments, the wound-treating composition of the inventionis essentially free of C1 to C6 alcohols (but not including polyols,such as glycerin or propylene glycol). In certain embodiments, thewound-treating composition is essentially free of C1 to C5 alcohols (butnot including polyols, such as glycerin or propylene glycol). In certainembodiments, the wound-treating composition is essentially free of C1 toC4 alcohols (but not including polyols, such as glycerin or propyleneglycol). By essentially free it is meant that such alcohols may bepresent in minor amounts, as may be useful for example for compounding,but are not present in an amount that one of skill in the art ofpharmaceutical wound-treating composition formulating would select tostabilize components of the composition. In these embodiments, theamount of such alcohols is less than about 8 wt %. In certainembodiments, the amount of such alcohols is less than about 5%, or 2%,or 1%, or 0.5%, or 0.25% (wt/wt).

When worked into the skin, the compositions of the invention can haverapid absorption—contributing to their non-greasy and non-watery feels.The compositions can be easy to spread and are cosmetically elegant.

While the wound-treating compositions can contain active ingredients,such as antimicrobial agents, surprisingly the wound treating efficacycan be obtained without such agents, using only components that are nottraditionally regarded as active ingredients. While not being bound bytheory, it is believed that this efficacy is due to (a) physicallyproviding a protective artificial barrier on the affected surface; (b)providing moisture to the skin/mucosa and improving its hydration; and(c) effectively controlling the inflammation in the affected area.

The composition contains fatty acids, which can be substantially oressentially ionized, wherein the salt may be more soluble or suspendablein the aqueous solvent of the composition. The fatty acids are, incertain embodiments, non-greasy, meaning that in the aggregate of theformulation, as formulated in the wound-treating composition, they arenon-greasy.

The fatty acid can, for example, be of any composition found in anatural source, including hydrolysis of esterified fatty acids. Or, thefatty acid component can be hydrogenated to remove substantially all ora portion of any unsaturation. In certain embodiments, the fatty acidcomponent is selected such that 50 mole % or more is C12 or higher, orC14, or C16 or higher. In certain embodiments, the fatty acid componentis selected such that 50 mole % or more is C22 or lower, or C20 orlower, or C18 or lower. In certain embodiments, 75 mole % or more of thefatty acid component is from C12 or C14 or C16 to C22 or C20 or C18. Incertain embodiments, 80 mole % or more, 85 mole % or more, 90 mole % ormore, 95 mole % or more, 97 mole % or more, 98 mole % or more, or 99mole % or more, meets one of the size parameters of this paragraph.

Useful salts of the fatty acids include the alkali metal salts such assodium or potassium salts; ammonium salts; salts formed with suitableorganic bases, such as amine salts (such as triethyl amine, triethanolamine, or the like) and quaternary ammonium salts; or the like. Bivalentor trivalent salts can be used where they do not adversely affectsolubility. As needed, the fatty acid components are provided such thata sufficient amount of constituent ionizable molecules are in ionized(salt) form to provide solubility. Such ionized forms can be prepared byadding a titrant. Recitations of compositions described by theirformation by titration include the equivalent compositions formed bypre-formed salts or otherwise.

In certain embodiments, the fatty acid(s) comprise an amount of E ormore, F or less, of from E to F of the wound-treating composition, whereE is 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6 wt %, and F is2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9 or 10 wt %. Unless otherwise specified, thecomposition percentages for the wound-treating compositions areexclusive of any propellant, such as propane or butane or the like.

An emollient, if present, can be a silicone oil such aspolydimethylsiloxane (i.e., dimethicone), petrolatum (natural orsynthetic), or the like. In certain embodiments, the emollient(s) are anamount I or more, J or less, or I to J of the wound-treatingcomposition, where I is 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4 wt %, and J is 0.6,0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 wt %.In certain embodiments, as among emollients and fatty acids in thewound-treating composition, the amount of emollient is an amount K ormore, L or less, or K to L of the emollients and fatty acids, where K is5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 wt %, and Lis 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24 or 25 wt %. Relative amounts of any petrolatum can be selected tominimize comedogenicity. In certain embodiments, silicone oil is a majorportion of the emollient component by weight. In certain embodiments,silicone oil is 80, 85, 90, 95, 96, 97, 98, 99, 99.5% or more of theemollient component (by weight).

The wound-treating composition will typically include emulsifyingagents. Emulsifying agents can be non-ionic detergents, such aspolyoxyethylene sorbitan fatty acid esters (such as Tween 80(polyoxyethylene (20) sorbitan monolaurate), Polysorbate 20(polyoxyethylene (20) sorbitan monooleate)), sorbitol fatty acid esters,octyly glucosides, PEGylated lipids and the like. In certainembodiments, the emulsifying agent(s) comprise an amount of M or more, Nor less, of from M to N of the wound-treating composition, where L is0.5, 0.6, 0.7, 0.8, 0.9, 2, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9or 2 wt %, and N is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9 or 4 wt %. The emulsifying agent(s) can comprisedetergents with 2 or more, 3 or more, 4 or more, 5 or more folddifference in CMC. The emulsifying agents can, for example, have a CMCat 21° C. of 2×10⁻⁶M to 10⁻⁴M. In certain embodiments, where there aretwo or more frothing agents, the predominant (by wt) frothing agent canhave the lower CMC vs the next most predominant frothing agent.

Hydrophilic polymer(s) can be present. These can be any non-toxic watersoluble polymer(s) that (in the aggregate) stabilize wound-treatingcomposition and contribute to film formation on the skin. Examplesinclude polyvinyl pyrrolidone, polyethylene glycol, starch,water-soluble derivatives of starch, cellulose, methyl cellulose,hydroxymethylcellulose, other water-soluble derivatives of cellulose,carbomers, or the like. For polyvinyl pyrrolidone, for example, usefulaverage molecular weights include from 8,000 to 63,000, such as about38,000. For all polymers used in the composition, the size can besufficient to limit penetration of the horny layer of the skin, if skinpenetration is an issue for the given polymer. In certain embodiments,hydrophilic polymer(s) are an amount I or more, J or less, or I to J ofthe wound-treating composition.

The composition can also contain a humectant, such as glycerol,propylene glycol, other polyols, polydextrose, lactic acid, or the like.In certain embodiments, humectant(s) are an amount O or more, P or less,or O to P of the wound-treating composition, where O is 4, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2,7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8 wt %, and P is 5, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1,11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9 or 12 wt %.

The wound-treating composition can optionally contain a preservative orpreservative system. Examples include Phenonip™ XB (a mixture ofpreservatives, believed to include phenoxyethanol, methylparaben,ethylparaben, butylparaben, propylparaben and isobutylparaben; fromClariant UK Ltd., Leeds, UK), or a less complex preservative, such asone or two of methylparaben, ethylparaben, butylparaben, propylparaben,isobutylparaben, benzalkonium chloride, imidurea or the like.

The wound-treating compositions will typically contain titrating agentssuch as trolamine, NaOH, citrate, phosphates, and the like. The amountis typically selected to provide a dermatologically or physiologicallyacceptable pH, such as pH 4-9, or 5-9, or 6-9.

The wound-treating compositions can be formulated as sprays, creams,lotions, milks, foam-formers, and the like. Where creams or lotions aredesired, these consistencies can be obtained by selection of hydrophilicpolymers, and the amounts thereof. For example, these can includepolymers that have a greater effect on increasing viscosity, inappropriate amounts. Such polymers can include, for example, appropriatecarbomers, carbopols, methylcellulose, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hypromellose, polyethylene glycol, polyethylene oxide,xanthan gum, Arabic gum, pectin, starch, alginate and the like. Additionof suitable hydrophilic co-polymer permits the formation of differentforms that retain the same safety and efficacy properties as thefoam-forming formulations but do not require the use of gaseouspropellants for their delivery to the treatment area. In suchembodiments, it may be that the amounts of polymer are to the high endor greater than those amounts discussed above.

Suitable propellants include, for example, propane, butane, isobutene,other hydrocarbons, hydrofluorocarbons, chlorofluorocarbons(Cl/F/(H)/C), and the like. Dispensing devices include those availablefrom Deutsche Präzision, Lindal Group (Schönberg, Germany), Coster(Milano, Italy) and SeaquistPerfect Dispensing (Cary, Ill.).

The formulation of the invention is, in certain embodiments, a stableemulsion. In others, the formulation provides an emulsion whenshaken/agitated prior to use. For certain of the foam embodiments, theformulation should be shaken/agitated prior to use. Certain foamembodiments provide a foam that is relatively stable at 35° C., such asstable for 1 or more minutes, or 2 or more minutes, or 3 or moreminutes, a period of time allowing for convenient transfer of the foamfrom a gloved or naked hand to the tissue to be treated. In certainembodiments, including certain thermally stable embodiments, the foambreaks, i.e., loses its foam texture, on application of the shear usedto manually apply the foam to the tissue.

Formulations of the invention have been found to be remarkablyantimicrobial. As such, they can be used prepare skin or mucosa fortreatments that are skin or mucosa piercing, such as surgery, IVs,needle biopsies, acupuncture, and the like, or for treating wounds orother dermatological conditions complicated by bacterial infection.

For example, forearm areas were treated with formulation for 5, 10, 20or 40 minutes, then challenged with ˜10⁵ CFU of Escherichia coli (ATCC#11229) or Staphylococcus aureus aureus MRSA (ATCC #33593). Microbialcolonization was inhibited to a statistically significant extent after10 minutes exposure or more for Staph. aureus MRSA, and after 20 minutesor more for E. coli.

In certain embodiments, the formulation can contain an alkyl pyridiniumchloride surfactant, such as cetylpyridinium chloride. The amount can,for example, be 0.25% wt or more, or 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9or 1% wt or more. The amount can, for example, be 4% wt or less, or 3.5,3.0, 2.5, 2.0, 1.5, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5% wt orless. Various antimicrobial agents can be further added.

In certain embodiments, the compositions used in the methods of theinvention lack any antimicrobial compounds, where the emollient, fattyacid, humectant and emulsifying agents are present in amountsappropriate to provide skin moisturization, skin barrier repair (fattyacid), and the texture properties desired (spray, cream, and the like).In certain embodiments, the emollient, fatty acid, humectant andemulsifying agents are present in amounts appropriate to provide one ormore of non-irritation, non-sensitization or non-comedogenicity. Incertain embodiments, the emulsifying agent consists essential of (noother present in amounts beyond minor amounts such as 0.1% by wt used tofacilitate making intermediate formulations used in the formulationprocess) nonionic detergent(s). The nonionic detergents can be thosewhere polyoxyethylene and or sugar moieties provide the hydrophilicportion, and hydrocarbons (e.g., alkanyl or alkenyl) provide thehydrophobic portion. In certain embodiments, the compositions used inthe methods of the invention lack any antimicrobial compounds other thanan alkyl pyridinium chloride surfactant, where the emollient, fattyacid, humectant and emulsifying agents are present in amountsappropriate to provide skin moisturization, skin barrier repair (fattyacid), and the texture properties desired (spray, cream, and the like).

One can test antimicrobial effect in an in vitro time kill method, suchas by mixing 0.1 mL challenge bacterial suspension with 9.9 g of testproduct. After one minute, 1.0 mL of the mix is added to 9.0 mL ofButterfield's Phosphate Buffer, with neutralizers where applicable.Serial dilutions into the same buffer are plated onto Tryptic Soy agarplates.

To formulate 100 g, one can for example formulate all or a selection ofthe formulations defined by the combinations of the following options:

TABLE A Component Amt. Options (g) A1 Water Quantity sufficient A2Povidone 1-3 A3 Stearic acid 5-8 A4 Propylene glycol 4-7 A5 Glycerol 1-2A6 Dimethicon 0.5-5   A7 Triethanol amine 0-3 A8 Polysorbate 20 1.3-5.0A9 Preservative   0-2.0

The above can be formulated by heating A1 and adding stepwise A2-A9while stirring. When homogeneous the formulation is cooled to roomtemperature or similar and formulations can be tested for foam forming(if appropriate), foam stability (if appropriate), non-wet feel,irritation, non-greasy feel, and the like.

In another embodiment, to formulate 100 g, one can for example formulateall or a selection of the formulations defined by the combinations ofthe following options:

TABLE B Component Amt. Options (g) C1 Povidone or thickening agent 0-3C2 Polysorbate 20 1.3-5.0 C4 Stearic acid  2-10 C5 Sodium citrate 0-3 C6Glycerol 1-2 C7 Triethanol amine 0-3 C8 Preservative 0-2 B  NaOH 0-1 D Povidone or thickening agent 0-3 A2 Dimethicon 0.5-5   A1 Propyleneglycol 4-7 A3 Tween 80 0-5 A4 Polysorbat 20 0.5-5   Water QuantitySufficient

The above can be formulated in 4 phases: mixing the A components; mixingB in a minor amount of the water; mixing D in a minor amount of thewater, mixing the C components in the bulk of the water; adding themixed A components to the mixed C components; and adding the mixed Bcomponents and finally the mixed D components. The A components can beadded to A1 stepwise in the order A2 to A4. The C components can beadded to water stepwise in the order C1 to C8, with the water heated topromote mixing and solubilization. The mixed B components can be addedto heated mixed C components. The mixed A components can be added inparts to the mixed C components, such as after the mixed A componentshave cooled, but still have an elevated temperature (over r.t.). Themixed D components are added (to A+B) after further cooling. Theformulations can be tested for foam forming (if appropriate), foamstability (if appropriate), non-wet feel, irritation, non-greasy feel,and the like.

In certain embodiments, a further thickening agent (e.g., thehydrophilic polymers discussed above) can be added in order to create agel, cream or a lotion. The above can be formulated in 2 phases: mixingthe B component in a minor amount of the water separately. The Acomponents are added to the rest of the heated water stepwise duringstirring. Where appropriate a pH adjustment can be made to the phase byuse of acid or base. The A phase and the B phase are mixed at the laststep and the formulation cooled to ambient.

TABLE C Component Amt. Options (g) B1 Thickener 1 0.05-2.0  A1 Thickener2 1-3 A2 Stearic acid 5-8 A3 Propylene glycol 4-7 A4 Glycerol 1-2 A5Dimethicon 0.5-5   A6 Triethanol amine 0-3 A7 Polysorbate 20 1.3-5.0 A8Preservative   0-2.0 A9 Water Quantity sufficient

EXAMPLES Example 1 Wound Care

One of the compositions of Table A was tested in a wound treatmentmodel. This composition is designated Test Article in the text below.

Animal Care

Experimentally naive female Domestic Yorkshire crossbred swine, at least9 weeks of age at receipt, were used. The animals were originallyreceived from Whiteshire Hamroc, Albion, Ind. Prior to use in the study,the animals were weighed weekly and observed with respect to generalhealth and any signs of disease. Ova and parasite evaluations on stoolsamples were performed, and all results were negative for animals placedin the study.

The animals were individually housed in runs with raised flooring. Thistype of housing provided adequate room for exercise for these animals.Fluorescent lighting was provided for approximately 12 hours per day.Temperature and humidity were continuously monitored and recorded. Theprotocol-designated ranges were 61 to 81° F. and 30 to 70%,respectively. Diet (Certified Lab Diet® #5K99, PMI NutritionInternational, Inc.) was offered via limited feedings, except duringdesignated periods. Tap water was available ad libitum via an automaticwatering system.

Wounding Procedure

The animals were fasted overnight prior to surgery and treated asspecified in Table C. Prior to surgery, the appropriate drugs wereadministered and general anesthesia was induced. A cuffed endotrachealtube was placed and general anesthesia was maintained with isofluranedelivered in oxygen through a rebreathing system with ventilator assist.

TABLE C Procedure-related Medications and Dose Levels Interval. DoseLevel. and Route Medication Surgery (Day 0) Daily PostsurgeryAcepromazine 0.1 mg/kg IM — maleate Atropine sulfate 0.05 mg/kg IM —Telazol 5 mg/kg IM — Isoflurane To effect, inhalation — Buprenorphine0.02 mg/kg IM 0.01 mg/kg IM TID × 3 days Cefazolin 25 mg/kg IV —Ceftiofur 2.2 mg/kg IM 2.2 mg/kg IM SID × 5 days Lactated Ringer's 5 to6 mL/kg/hour IV — Solution (LRS) IM—Intramuscular IV—IntravenousTID—Three times daily SID—Once daily

All surgical procedures were performed utilizing routine aseptictechnique. Following induction of anesthesia, the entire dorsal surfacewas prepared for surgery with Iodine Scrub, 70% isopropyl alcohol, andIodine solution.

Following completion of preoperative procedures on Day 0, six 2.5 cm×2.5cm wound sites were marked out, three on either side of the dorsalmidline caudal to the scapula and 2.5 cm (animal numbers 101 and 102) or5 cm (animal numbers 103 and 104) from the midline, using sterile skinmarker pens. The wounds were separated from each other (approximately 5cm) to avoid wound to wound contact. To avoid cross-contamination ofTest Article treated wounds with wound treated by Positive ControlArticle (Biafine Ointment, OrthoNeutrogena) [purified water, liquidparaffin, ethylene glycol monostearate, stearic acid, propylene glycol,paraffin wax, squalene, avocado oil, trolamine sodium alginate, cetylpalmitate, methylparaben (sodium salt), sorbic acid (potassium salt),propylparaben (sodium salt) and fragrance] and Standard Care (RELEASE®non-adherent absorbable dressing, Johnson & Johnson), the Standard Carewound sites were wounded first, followed by the Positive Control Articlewounds and then Test Article. The skin covering the wound site and thedermatome-was moistened with sterile saline using sterile gauzeimmediately prior to each wound to aid the running of the dermatome. Six2.5 cm×2.5 cm×0.50 mm (length×width×depth) split thickness skin graftwounds were created using the dermatome; three wounds were created oneach side of the dorsal midline.

If necessary, a pair of scissors was used to aid in the removal of skin.The portion of the dermatome in contact with the skin was frequentlycleaned with chlorhexadine, and then rinsed with sterile saline. Thedermatome blade was changed following completion of the wounding in eachpig, prior to commencement of wounding the subsequent pig. Following thecompletion of wounding, a piece of dry sterile gauze was placed on eachwound to absorb excess blood. Following removal of the sterile gauze theappropriate treatment was applied to the wound. The Positive Control andTest Article were applied to each designated wound site by spreadingevenly with a sterile spatula (dose volume of approximately 4 mg/cm², 25mg). A piece of non-adherent absorbable dressing (Johnson & Johnson) wasplaced on each wound. The non-stick dressings on each side of the pigwere held in place using a sheet of Bioclusive transparent dressing(Johnson & Johnson). The Bioclusive was carefully placed on the wounds,ensuring that it was not pulled too taught to avoid skin irritation.Care was taken to seal the Bioclusive dressing around the four edges ofeach non-stick dressing. Following the placement of the Bioclusivedressing, the wounds were dressed with Elastikon® elastic tape (Johnson& Johnson): A Surgilast (Glenwood, Inc., Tenafly, N.J.) equivalent toSurgifix (FRA Production S.p.A., Cisterna D'Asti, Italy) stocking wasplaced on the body of the animal.

Monitoring was conducted during anesthetic recovery for physiologicaldisturbances including cardiovascular/respiratory depression,hypothermia, and excessive bleeding from the surgical site. Theendotracheal tube was removed after the animal regained the swallowreflex. Long-term postoperative monitoring included daily inspection ofsurgical sites. Medications were administered as presented in Table C.

Wound Administrations

The treatments, Standard Care Dressing (sterile gauze bandage), PositiveControl, and Test Article, were administered via topical application tosix split thickness skin graft wounds created on the dorsum of the pig.Treatments were administered once daily for 14 days at a dose volume ofapproximately 4 mg/cm² (approximately 25 mg). Wounds were randomlytreated with each of the three treatments in a manner that allowed eachanimal to receive two sites treated with each treatment.

On each day of the study (Days 1 to 14), Telazol (5 to 6 mg/kg, IM) wasadministered and anesthesia was maintained with isoflurane delivered inoxygen. The bandages were then removed. For the Standard Care treatedwounds, the Surgifix stocking or equivalent and Elastikon® elastic tapewere removed. The Bioclusive transparent dressing and non-adherentabsorbable dressing was then removed from the wound. The site wascarefully cleaned with sterile saline and gauze. Following cleaning, apiece of non-adherent absorbable dressing was placed on each wound. Thenon-stick dressings on each side of the pig were held in place using asheet of Bioclusive transparent dressing. The Bioclusive was carefullyplaced on the wounds, ensuring that it was not pulled too taught toavoid skin irritation. Care was taken to seal the Bioclusive dressingaround the four edges of each non-stick dressing. Following theplacement of the Bioclusive dressing, the wounds were dressed withElastikon® elastic tape. A Surgifix stocking or equivalent was placed onthe body of the animal.

For the Positive Control treated wounds, the Surgifix stocking orequivalent and Elastikon® elastic tape was removed. The Bioclusivetransparent dressing and non-adherent absorbable dressing was thenremoved from the wound. The site was carefully cleaned with sterilesaline and gauze to remove any residual material. Following cleaning,the site was dosed and a piece of non-adherent absorbable dressing wasplaced on each wound. The non-stick dressings on each side of the pigwere held in place using a sheet of Bioclusive transparent dressing. TheBioclusive was carefully placed on the wounds, ensuring that it was notpulled too taught to avoid skin irritation. Care was taken to seal theBioclusive dressing around the four edges of each non-stick dressing.Following the placement of the Bioclusive dressing, the wounds weredressed with Elastikon® elastic tape. A Surgifix stocking or equivalentwas placed on the body of the animal.

For the Test Article treated wounds, the Surgifix stocking or equivalentand Elastikon® elastic tape was removed. The Bioclusive transparentdressing and non-adherent absorbable dressing was then removed from thewound. The site was carefully cleaned with sterile saline and gauze toremove any residual material. Following cleaning, the site was dosed anda piece of non-adherent absorbable dressing was placed on each wound.The non-stick dressings on each side of the pig were held in place usinga sheet of Bioclusive transparent dressing. The Bioclusive was carefullyplaced on the wounds, ensuring that it was not pulled too taught toavoid skin irritation. Care was taken to seal the Bioclusive dressingaround the four edges of each non-stick dressing. Following theplacement of the Bioclusive dressing, the wounds were dressed withElastikon® elastic tape. A Surgifix stocking or equivalent was placed onthe body of the animal.

Erythema and Edema

The wound and skin around the wound was assessed for the presence oferythema and edema. Assessment of erythema and edema was made after thewound had been gently cleaned, if needed, ensuring no damage was caused.Assessment of erythema and edema was graded on the following 5 pointscales, according to Draize (Draize J H, Woodard G, Calvery H O. Methodsfor the study of irritation and toxicity of substances applied topicallyto the skin and mucous membranes. J Pharmacol Exp Ther 1944; 82:377-390,1959) 4 point acute dermal irritation scale.

TABLE F Erythema Formation Score Observation 0 No erythema 1 Very slighterythema (barely perceptible) 2 Well-defined erythema 3 Moderate tosevere erythema 4 Severe erythema (beet redness) to eschar formation(injuries in depth) Maximum possible score = 4

TABLE G Edema Formation Score Observation 0 No edema 1 Very slight edema(barely perceptible) 2 Slight edema (edges of area well-defined bydefinite raising) 3 Moderate edema (raised approximately 1 mm) 4 Severeedema (raised more than 1 mm and extending beyond area of exposure)Maximum possible score = 4

Results were:

TABLE J Individual Wound Healing Scores: Erythema Study Standard CarePositive Test Interval Dressing Control 1 Article (Days) Score (n = 8)(n = 8) (n = 8) 1 0-no erythema 8 7 8 1-very slight 0 1 0 2-well defined0 0 0 4 0-no erythema 6 5 6 1-very slight 2 3 1 2-well defined 0 0 1 70-no erythema 4 7 7 1-very slight 4 1 1 2-well defined 0 0 0 10 0-noerythema 5 5 7 1-very slight 3 3 1 2-well defined 0 0 0 14 0-no erythema4 5 7 1-very slight 4 3 1 2-well defined 0 0 0 No sites were scoredgreater than 2 and as such the data is not presented in the summarytable.

TABLE K Individual Wound Healing Scores: Edema Study Standard CarePositive Test Interval Dressing Control 1 Article (Days) Score (n = 8)(n = 8) (n = 8) 1 0-no edema 8 8 8 1-very slight 0 0 0 4 0-no edema 7 65 1-very slight 1 2 3 7 0-no edema 6 8 8 1-very slight 2 0 0 10 0-noedema 8 8 8 1-very slight 0 0 0 14 0-no edema 8 8 8 1-very slight 0 0 0No sites were scored greater than 1 and as such the data is notpresented in the summary table.

Exudate

The wound and skin around the wound was assessed for the presence ofexudate. Assessment of exudate was made after the wound had been gentlycleaned, if needed, ensuring no damage was caused to the wound in doingso. Assessments were graded according to the following 5 point scale.The results were:

TABLE L Individual Wound Healing Scores: Exudate Study Standard CarePositive Test Interval Dressing Control 1 Article (Days) Score (n = 8)(n = 8) (n = 8) 1 0-none 0 0 0 1-mild 0 1 1 2-moderate 7 7 7 3-severe 10 0 4 0-none 0 0 0 1-mild 2 2 2 2-moderate 6 6 5 3-severe 0 0 1 7 0-none4 7 8 1-mild 4 1 0 2-moderate 0 0 0 3-severe 0 0 0 10 0-none 8 8 81-mild 0 0 0 2-moderate 0 0 0 3-severe 0 0 0 14 0-none 8 8 8 1-mild 0 00 2-moderate 0 0 0 3-severe 0 0 0 No sites were scored greater than 3and as such the data is not presented in the summary table.

Wound Size

Digital photographs of the site of surgery were taken on Days 4, 7, 10,and 14 during dressing changes and prior to necropsy. Photographs weretaken after dressings had been removed and the wound had been gentlycleaned, if needed, ensuring no damage was cause to the wound in doingso. For all photographs, a measurement scale was place in the same planeas the surgical sites. Morphometry was performed in the wound area todocument changes in wound size. Morphometry was used to determineadvancement of wound edge, reduction in total area/percent closure, andtime to complete healing.

On Days 4, 7, 10, and 14, digital photos were taken of each wound andthe wound area was measured by tracing the edge of the wound. When thewound was considered to be completely healed, the area measurement was0. The results were:

TABLE M Average Wound Area (mm²) Time point Treatment Day 4 Day 7 Day 10Day 14 Standard Care Mean Area 590.1 177.6 115.5 0.0 SD 39.93 232.11135.17 0.00 Positive Control Mean Area 616.4 44.3 87.7 0.0 SD 45.48101.97 165.58 0.00 Test Article Mean Area 632.2 18.8 0.0 0.0 SD 57.0039.00 0.00 0.00

The results of this study demonstrate that application of the TestArticle (a cream according to the invention) daily to a split thicknessskin graft wound in the pig does not adversely affect wound healing.Application of the Test Article was found to reduce the incidence oflocalized erythema and reduce the amount of time that exudate waspresent at the site of injury. When evaluated for time to completeclosure of the wound, application of the Test Article was found toaccelerate healing. Wounds treated with the test article achievedcomplete closure by Day 7-10 post injury, whereas wounds treated withthe standard of care required 10-14 days. At 7 days, wounds treated withthe positive control article appeared to be healing at the same rate aswounds treated with the Test Article. By Day 10, three of these woundshad reopened suggesting that wounds treated with the Test Article hadbetter durability of closure. This effect is mirrored in the evaluationof wound area. Application of the Test Article daily to the wounds wasfound to substantially reduce the size of the wound over time. Uponmicroscopic evaluation, a slight decrease was noted in subacuteinflammation, the degree of neovascularization, and granulomatousinflammation in the Test Article treated wounds. The results of thisstudy demonstrate that application of the Test Article providesaccelerated healing with reduced localized erythema and inflammation.

Example 2 Irritation as Measured by the Method of Lanman et al

The Lanman et al. method of irritation measurement was conducted with acream of the invention (“Test Cream”). The objective of this study wasto compare the relative cumulative irritation potential of topicallyapplied cream to a negative (Johnson's® Baby Oil) and a positive (0.2%v/v Sodium Lauryl Sulfate) control following repetitive dailyapplications to the skin of normal healthy, adult volunteers. This was asingle center, test site randomized, clinical trial designed to evaluatethe relative cumulative irritation potential of these test articles. Thecompositions used were the Test Cream, Johnson's® Baby Oil and 0.2%Sodium Lauryl Sulfate (v/v in DI water). These were rubbed in to theupper back between the left and right infra-scapular areas and thencovered with a blank semi-occlusive patch. Application sites wererandomized as to their position on the subjects' backs to eliminate testsite bias. Products were rubbed in and blank semi-occlusive patches wereapplied to the same sites every day for twenty-one (21) consecutive daysfor a total of 21 applications. Each patch was worn for approximately 24hours, removed under clinical supervision and the test sites evaluatedapproximately 10 minutes following patch removal. Briefly, undersemi-occlusive conditions and for up to 21 days, the data revealed thatTest Cream was very well tolerated (non-irritating) and its tolerabilitywas comparable to Johnson's Baby Oil (Negative Control).

Example 3 Sensitization

The ISO 10993-10: 2002 method was used to evaluate the allergenicpotential or sensitizing capacity of a foam formulation of the invention(“Test Foam”), by screening of contact allergens in guinea pigs andextrapolating the results to humans. In the Induction Phase, ten testguinea pigs were patched with the Test Foam and 5 guinea pigs werepatched with the negative control article, removed after at least 6 hourexposure. After a 24-hour rest period, each site was observed forerythema and edema. The procedure was repeated 3 times per week for 3weeks. In the Challenge Phase, following a 2 week rest period, theanimals were topically patched again, removed after at least 6 hours ofexposure. Dermal patch sites were observed for erythema and edema 24 and48 hours after patch removal. Each animal was assessed for asensitization response and test results were based upon incidence andseverity of the sensitization reaction.

None of the animals showed abnormal clinical signs during the testperiod. There was no irritation observed on the Test Foam and controlanimals during the induction phase. The dermal response incidence was0%. None of the test animals challenged with the Test Foam was observedwith a sensitization response at any time point, indicating a 0%incidence. The severity was calculated as 0 at each time point. Theincidence of dermal response to repeat patch sensitization testing forthe Test Foam was zero in the study demonstrating that the Test Foamdoes not cause dermal sensitization.

Example 4 Comedogenicity

Using the method for measuring comedogenicity detailed above, acomposition of the invention and a negative control producedsignificantly less microcomedones than a positive control (P=0.003 andP=0.037, respectively) and the number of microcomedones at the sitestreated with the composition was not significantly different from thenumber of microcomedones observed at the negative control sites.

Example 5 Antibacterial Effect

Twenty subjects were evaluated, ten subjects per each of the challengespecies. Upon completion of a 7-day product restriction period, atrained technician applied the test formulation to the skin of onerandomly assigned forearm. The subjects' other forearms served asuntreated controls and received no test formulation. Four sites weredelineated on the skin of each forearm and, 10 minutes following theproduct application procedure, the sites were exposed to the randomlyassigned challenge suspension for contact times of 5 minutes, 10minutes, 20 minutes, and 40 minutes and then sampled. Contaminated siteswere not occluded, but subjects were sequestered for the duration of theevaluation.

The 7 days prior to the test portion of the study constituted thepre-test period. During this time, subjects avoided the use of medicatedsoaps, lotions, deodorants and shampoos, as well as skin contact withsolvents, detergents, acids and bases, or any other products known toaffect the normal microbial populations of the skin. Subjects weresupplied a personal hygiene kit containing non-medicated soap, shampoo,lotion, and rubber gloves to be worn when contact with antimicrobials,solvents, detergents, acids, or bases cannot be avoided. Subjects wereinstructed to use the contents of this kit exclusively during theirparticipation in the study. Subjects also avoided using UV tanning bedsor sunbathing, and swimming or bathing in biocide-treated pools or hottubs.

Escherichia coli (ATCC #11229) and Staphylococcus aureus aureus MRSA(ATCC #33593) were used to challenge the efficacy of the testformulation.

Approximately 48 hours prior to initiating the study, sterile tubes ofTryptic Soy Broth (TSB) were inoculated from cryogenic stock cultures orlyophilized vials containing E. coli and Staph. aureus MRSA. Themicroorganism cultures were incubated at 30°±2° C. for approximately 24hours. Approximately 24 hours prior to initiating the study, the brothcultures were inoculated onto the surface of Tryptic Soy Agar (TSA) andincubated at 30°±2° C. for approximately 24 hours. Immediately prior toinitiating the test procedure, suspensions of bacteria were prepared bytransferring growth from the cultures on TSA into test tubes containingsterile Phosphate Buffer Solution (PBS). Suspension concentrations ofapproximately 1.0×10⁹ CFU/mL were prepared, determined on the basis ofturbidity. Serial dilutions of the challenge suspension were made in PBSto achieve a final challenge inoculum of approximately 1.0×107 CFU/mL.The final challenge inoculum was assayed for number of organisms at thebeginning and at the end of the use period.

The left or right forearm was randomized to treatment with the testformulation, and the remaining forearm served as the untreated control.Following demarcation (see below), the four test sites on the skin ofeach forearm were assigned randomly and bilaterally to post-treatmentsample times. Prior to sampling, the subjects were questioned regardingadherence to the protocol. Subjects were examined physically to ensureno evidence of injury was present on the skin of the forearms. The skinof the forearms was rinsed with 70% isopropyl alcohol (IPA) and allowedto air-dry. A technician selected and marked with an indelible inkmarker four test sites on the volar surface of each forearm within a 2inch by 7 inch area. The sites were spaced uniformly, startingsequentially (one through four) from the elbow moving distally towardthe wrist, and the ink was allowed to dry thoroughly before continuing.1.0 mL of the test formulation was then applied to all four sites on therandomly-assigned forearm and a gloved hand was used to distribute theproduct evenly over all test sites. Any test formulation that dripped tothe underside of the arm was wiped with a paper towel. The test sites onforearms assigned as untreated control were not treated with testformulation.

10 minutes±1 minute following application of test formulation (orfollowing the initial decontamination of the untreated control), thefour test sites were exposed to 10 microliter of the challengesuspension of E. coli or Staph. aureus MRSA. Following 40 minute±1minute exposure, 20 minute±1 minute exposure, 10 minute±1 minuteexposure, and 5 minute±1 minute exposures, individual sites were sampledusing the Cylinder Sampling Technique and then decontaminated with 70%IPA.

The cylinder sampling technique was performed as follows:

At the designated time, a sterile cylinder with an inside area of 3.46cm2 was held firmly onto the test site to be sampled. 2.5 mL of sterileStripping Suspending Fluid with appropriate product neutralizers (SSF++)was instilled into the cylinder, and the skin area inside the cylindermassaged in a circumferential manner for 1 minute with a sterile rubberpoliceman.

The 2.5 mL of SSF++ was removed with a pipette and transferred to asterile test tube. A second 2.5 mL aliquot of SSF++ was instilled intothe cylinder, and the skin area again massaged for 1 minute with arubber policeman.

The second 2.5 mL aliquot was pooled in the test tube with the firstaliquot.

Subjects were not allowed to leave the laboratory for any reason oncethe testing began. Additionally, subjects were required to wearprotective garments and not touch their clothing, faces, or any otherbody parts with their forearms during the test period. On completion oftesting, subjects were required to perform a I-minute rinse of theirforearms with 70% ethanol and an air dry, followed by a supervised4-minute wash with a 4% chlorhexidine gluconate solution. A topicalantibiotic ointment was applied to the forearms following thedecontamination procedure.

Duplicate spiral plates or duplicate spread plates were prepared fromcylinder samples (10° dilution) on MacConkey Agar (MAC) for Escherichiacoli (ATCC #11229) and Hardy Chrom Staph aureus (CHROM) forStaphylococcus aureus aureus MRSA strain (ATCC #33593). These wereincubated at 30°±2° C. for approximately 48 hours and at 35°±2° C. forapproximately 24 hours, respectively, or until sufficient growth wasobserved. Colonies were counted and data recorded using the Q-Countplate counting system or equivalent.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

What is claimed is:
 1. A method of accelerating wound closure in amammalian subject, the method comprising: administering topically aneffective amount of a water-based formulation to a wound that isselected from the group consisting of incisions, abrasions, lacerations,penetration wounds, burns, ulcerations, surgical wounds, and piercingwounds, the water-based formulation comprising: an emollient comprisinga silicone oil or a petrolatum, a fatty acid comprising stearic acid,one or more humectants comprising one or more of a glycerol and apropylene glycol, one or more emulsifying agents comprising polysorbate20, one or more hydrophilic polymers selected from the group consistingof: polyethylene glycol, starch, cellulose, and carbomers, and water,wherein the water-based formulation is formulated as a spray, cream,lotion, milk or foam-former, and wherein said administrating is for atime sufficient to substantially achieve wound closure.
 2. The method ofclaim 1, wherein the water-based formulation is applied as a foam usinga propellant.
 3. The method of claim 1, wherein the water-basedformulation is essentially free of C1 to C6 alcohols but not includingpolyols.
 4. The method of claim 1, wherein the water-based formulationfurther comprises a preservative.
 5. The method of claim 1, wherein thewater-based formulation is free of preservatives.
 6. The method of claim2, wherein the water-based formulation must be shaken prior to use. 7.The method of claim 2, wherein the foam is stable at 35° C. for at least1 min.
 8. The method of claim 1, wherein the water-based formulation isnon-irritating.
 9. The method of claim 1, wherein the water-basedformulation is non-sensitizing.
 10. The method of claim 1, wherein thewater-based formulation is non-comedogenic.
 11. The method of claim 1,wherein the water-based formulation comprises, by weight % of thecomposition: the one or more hydrophilic polymers in an amount in therange of 1.0-3.0%; stearic acid in an amount in the range of 5.0-8.0%;propylene glycol in an amount in the range of 4.0-7.0%; glycerol in anamount in the range of 1.0-2.0%; dimethicone in an amount in the rangeof 0.5-5.5%; triethanolamine in an amount in the range of 0.1-3.0%;polysorbate 20 in an amount in the range of 1.3-5.0%; preservative in anamount in the range of 0.0-2.0%; and water.
 12. The method according toclaim 1, wherein the water-based formulation comprises:
 0. 5 to 5 weight% of the emollient comprising silicone oil, and 2 to 10 weight % offatty acid comprising stearic acid.
 13. The method according to claim 1,wherein the water-based formulation further comprises one or moretitrants selected from a group consisting of triethanolamine, NaOH,citrate and phosphate.
 14. The method according to claim 1, wherein theadministering comprises administering topically the water-basedformulation two to three times a day to the wound in an amount of 1 to 5mg/cm².
 15. The method of claim 1, wherein the administering results inthe reduction in the incidence of erythema and/or edema in the wound.16. The method of claim 1, wherein the silicone oil ispolydimethylsiloxane.
 17. The method of claim 1, wherein the water-basedformulation further comprises one or more humectants selected from agroup consisting of polyols, excluding glycerol and propylene glycol,polydextrose and lactic acid.
 18. The method of claim 1, wherein thewater-based formulation further comprises one or more emulsifying agentsselected from a group consisting of sorbital fatty acid esters, octylglucosides and pegylated lipids.
 19. The method of claim 1, wherein thewound extends the full thickness of the skin.
 20. The method of claim 1,wherein the water-based formulation does not contain an activeanti-microbial ingredient.
 21. The method of claim 1, wherein thewater-based formulation consists of: the emollient comprising thesilicone or the petrolatum; the fatty acid comprising stearic acid; theone or more humectants comprising one or more of a glycerol andpolypropylene glycol; the one or more emulsifying agents comprisingpolysorbate 20; the one or more hydrophilic polymers selected from thegroup consisting of: polyethylene glycol, starch, cellulose, andcarbomers; one or more titrants; and water.
 22. The method of claim 1,wherein the water-based formulation consists of: the emollientcomprising the silicone or the petrolatum; the fatty acid comprisingstearic acid; the one or more humectants comprising one or more of aglycerol and polypropylene glycol; the one or more emulsifying agentscomprising polysorbate 20; the one or more hydrophilic polymers selectedfrom the group consisting of: polyethylene glycol, starch, cellulose,and carbomers; one or more titrants; one or more preservatives; andwater.
 23. The method of claim 1, wherein the water-based formulationconsists of: the emollient comprising the silicone or the petrolatum;the fatty acid comprising stearic acid; the one or more humectantscomprising one or more of a glycerol and polypropylene glycol; the oneor more emulsifying agents comprising polysorbate 20; the one or morehydrophilic polymers selected from the group consisting of: polyethyleneglycol, starch, cellulose, and carbomers; one or more titrants; anactive agent other than a microbial agent; and water.
 24. The method ofclaim 1, wherein the water-based formulation consists of: the emollientcomprising the silicone or the petrolatum; the fatty acid comprisingstearic acid; the one or more humectants comprising one or more of aglycerol and polypropylene glycol; the one or more emulsifying agentscomprising polysorbate 20; the one or more hydrophilic polymers selectedfrom the group consisting of: polyethylene glycol, starch, cellulose,and carbomers; one or more titrants; an active agent other than amicrobial agent; one or more preservatives; and water.
 25. The method ofclaim 1, wherein the water-based formulation consists of: the emollientcomprising the silicone or the petrolatum; the fatty acid comprisingstearic acid; the one or more humectants comprising one or more of aglycerol and polypropylene glycol; the one or more emulsifying agentscomprising polysorbate 20; the one or more hydrophilic polymers selectedfrom the group consisting of: polyethylene glycol, starch, cellulose,and carbomers; one or more preservatives; and water.
 26. The method ofclaim 1, wherein the water-based formulation consists of: the emollientcomprising the silicone or the petrolatum; the fatty acid comprisingstearic acid; the one or more humectants comprising one or more of aglycerol and polypropylene glycol; the one or more emulsifying agentscomprising polysorbate 20; the one or more hydrophilic polymers selectedfrom the group consisting of: polyethylene glycol, starch, cellulose,and carbomers; an active agent other than a microbial agent; and water.